Compositions, kits and regimens for the treatment of skin, especially décolletage

ABSTRACT

Compositions, kits and regimens for treatment of damaged skin, especially décolletage, include application of a retinoid, hydroquinone or hydroquinone derivatives, and a composition containing a multi-metal complex.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of and claimspriority to pending U.S. application Ser. No. 12/331,781 filed on Dec.10, 2008 which claims priority to U.S. Provisional Application No.61/019,047 filed on Jan. 4, 2008.

TECHNICAL FIELD

The present disclosure relates to compositions, kits and methods fortreating skin, especially décolletage. The method includes theapplication of a retinoid, hydroquinone or a hydroquinone derivative anda composition containing a multi-metal complex.

BACKGROUND

The problems associated with the complexion of décolletage are lessfrequently given attention, as compared with e.g. the face. Withadvancing age, however, wrinkles and pigmented spots can appear on thedécolletage. One approach that has been used in an attempt to reduce thesigns of aging of the décolletage is therapy with laser. In theory,exposure to the laser rays helps the collagen in the skin partlyrecover; with some old and damaged collagen filaments being absorbed andin about six weeks a new skin skeleton is established, with new collagenthat is more flexible. Pigmented spots, typical in the décolletage, maylikewise be removed by laser. Essentially, the laser energy passesthrough the surface of skin and disintegrates the pigment into minutefragments that are absorbed by the body after a short time. Anotherapproach to reduce wrinkles in the décolletage is by injecting thefilling materials. Each of these treatments requires application by aprofessional.

It would be desirable to provide a regimen for treatment of thedécolletage which is effective in reducing wrinkles, lightening agespots, is well tolerated by the skin and can be administered by the userwithout professional supervision.

SUMMARY

Regimens for treatment of damaged skin, especially décolletage, aredescribed which include application of a retinoid, hydroquinone and acomposition containing a multi-metal complex. The retinoid can betretinoin. The multi-metal complex contained is a compound having atleast two different metal cations in the same molecule and can be thereaction product of a polyfunctional acid with two or more coordinationelements.

In embodiments, the composition containing a multi-metal complexincludes at least one compound of a multifunctional carboxylic acidhaving copper and zinc cations in the same molecule which can be, forexample, copper-zinc citrate, copper-zinc oxalate, copper-zinctartarate, copper-zinc malate, copper-zinc succinate, copper-zincmalonate, copper-zinc maleate, copper-zinc aspartate, copper-zincglutamate, copper-zinc glutarate, copper-zinc fumarate, copper-zincglucarate, copper-zinc polyacrylic acid, copper-zinc adipate,copper-zinc pimelate, copper-zinc suberate, copper-zinc azealate,copper-zinc sebacate, copper-zinc dodecanoate, or combinations thereof.

In embodiments, hydroquinone and retinoid are applied as individualcompositions. In other embodiments, hydroquinone and retinoid areapplied as a single composition prepared by combining ahydroquinone-containing blending composition with a retinoid immediatelyprior to application to the skin as a pre-mixed composition. Oneparticularly useful blending composition contains hydroquinone (40mg/gm) (drug ingredient) in a base of water, glycerin, cetyl alcohol,PPG-2 myristyl ether propionate, sodium lauryl sulfate, TEA-salicylate,lactic acid, phenyl trimethicone, tocopheryl acetate, sodiummetabisulfite, ascorbic acid, methylparaben, saponins, disodium EDTA,BHT and propylparaben.

In embodiments, the regimen includes morning and evening applications,with the morning application including the sequential application of thehydroquinone-containing blending composition and a compositioncontaining a multi-metal complex and optionally a sun protectingcomposition and the evening application including the sequentialapplication of a first composition prepared by mixing a retinoid with ahydroquinone-containing blending composition and a second compositioncontaining a multi-metal complex.

The retinoid, hydroquinone, and composition containing a multi-metalcomplex may be packaged together in a kit. In embodiments, the kit maycontain the multi-metal complex, the retinoid, and the hydroquinone eachcontained in separate containers. In other embodiments, the kit mayinclude a first container containing the composition containing amulti-metal complex, a second container containing ahydroquinone-containing blending composition, and a third containercontaining a retinoid formulated for mixing with the blendingcomposition.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Compositions, kits and regimens for treatment of skin, especially thedécolletage, in accordance with the present disclosure include aretinoid, hydroquinone and a multi-metal complex and their applicationto a non-facial area of the skin of a user.

The Multi-Metal Complex-Containing Composition

The composition containing a multi-metal complex include a topicallyacceptable carrier and at least one multi-metal complex. The multi-metalcomplex is the reaction product of a polyfunctional compound (inembodiments a polyfunctional acid or an amino acid) with two or moredifferent coordination elements resulting in a compound having at leasttwo different metal cations in the same molecule.

The polyfunctional acid can be any compound that contains at least twoacid groups that may complex with metal cations in solution. The atleast two acid groups may be organic or inorganic acids, such as, forexample, two carboxylic acid groups or at least two phosphoric acidgroups. Polyfunctional acids are primarily monomeric compositions havingtwo or more carboxylic acid groups. Non-limiting examples ofpolyfunctional acids include maleic acid, fumaric acid, citric acid,citraconic acid, itaconic acid, glutaconic acid, phthalic acid,isophthalic acid, terephthalic acid, cyclohexane dicarboxylic acid,succinic acid, adipic acid, sebacic acid, azealic acid, malonic acid,dodecanedioic acid, 1,18-octadecanedioic acid, dimer acids (preparedfrom a mono-, di- or triunsaturated fatty acid, acid wax, acid anhydridegrafted wax, or other suitable polycarboxylic acid reacting compound),alkenyl succinic acids (such as n-dodecenylsuccinic acid, docecylcucinicacid and octadecenylsuccinic acid), azaleic acid, phytic acid and thelike. The polyfunctional acid can be present in acidic form, anhydrideform, partially neutralized salt forms, or mixtures thereof.

The polyfunctional acid is reacted with two or more coordinationelements. The coordination elements can be chosen from the elementslisted in Groups IIIA to VIIIA, Groups IB to IIIB, of periods 4 and 5and aluminum in Group IIIB, period 3 of The Periodic Table of theElements. Suitable non-limiting examples of elements listed in group IBof The Periodic Table of Elements include copper and silver. Suitablenon-limiting examples of coordination elements include aluminum,scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel,copper, zinc, gallium, yttrium, zirconium, niobium, molybdenum,technetium, ruthenium, rhodium, palladium, silver, cadmium, and indium.Tin may also be used. Those skilled in the art will readily envisionsuitable compounds for providing the coordination elements in thereaction mixture.

Non-limiting examples of compounds that may be used to providecoordination elements in the reaction mixture can include free metals,ammonium compounds, carbonates, hydroxides and oxide compounds of thecoordination elements. Suitable copper compounds include copper, copperhydroxide, copper borate, copper carbonate and copper oxide. Suitablezinc compounds include zinc metal, zinc oxide, zinc borate, zincmetaborate, basic zinc borate, zinc glycerophosphate, zinc citrate, zincpicrate and zinc hydrogen phosphate. It should be understood that thelisted compounds are only a small portion of the compounds suitable foruse in accordance with the present disclosure. For example, inorganiccompounds are suitable provided that they provide coordination elementcations when placed in an aqueous solution with the polyfunctionalcompound. Thus, the foregoing list of compounds should be considered anon-limiting, illustrative list.

For carrying out the process, a reaction solution can be prepared bymixing the various ingredients in water. Water in the mixture mayadvantageously be added in limited amounts sufficient to allow thereaction product to precipitate from solution upon formation. Wherenecessary, mixing and heating can be used to bring the reactants to40-100° C. in order to solubilize the reactants and start reactions. Asa result, reactant solubility may be enhanced through energy input suchas microwave heating or addition of boiling water. The input of theenergy may take place through any instrument capable of heating theaqueous reaction mixture. The reaction products formed in solution maybe immediately separated so that their production can take place in acontinuous process. Where a short reaction time and rapidcrystallization of the reaction product occur, the conversion may becarried out continuously, and the recovery of the resultant solidproduct may take place by any conventional manner such as filtering,centrifugation, or sedimentation.

The polyfunctional acid is present in the reaction mixture in amountsthat will contact metal cations in an aqueous solution. Suitable amountsof polyfunctional acid also include excess amounts in relation to theamount of metal cations. In embodiments, polyfunctional acid is presentin a 3:1:1 molar ratio in relation to the metal constituents. Inembodiments, the polyfunctional acid is malonic acid which can bepresent in acidic form, partial salt form, or mixtures thereof.

In embodiments, the process parameters are especially advantageous ifthe polyfunctional acid is added to excess in comparison to the metalcounter cation constituents. Depending on the desired complex, thelatter are added so that the molar ratio of polyfunctional acid to metalions is approximately 3:2.

In embodiments, the coordination elements may be present as one or moreionic compounds formed by joining one or more independent coordinationelement molecules or ions of a first type and coordination elementmolecules or ions of a second type to a central unit by ionic bonds. Forexample, the reaction product may be in the form of a trinuclear cation,where structurally independent coordination element hydrates are bridgedby a central unit. However, various coordination modes are possibledepending on the source of the coordination elements and synthesisconditions. In embodiments, the central unit may be a multi-memberedring such as eight-membered ring, six-membered ring, and four-memberedmetalocycle for bridging or chelating functions between the coordinationelement constituents. Accordingly, the crystal structures of thereaction products can be very diverse, from ionic to three-dimensionalpolymers. In embodiments, the reaction products are present in severalhydrate, and polymorphic forms.

In embodiments, suitable reaction products can be non-toxic multi-metalcomplexes that include copper, zinc, aluminum and/or silverconstituents. Such copper, zinc, aluminum and/or silver reactionproducts include, but are not limited to compounds that contain copper,zinc, aluminum and/or silver. Non-limiting examples of bimetal complexesinclude copper-zinc citrate, copper-silver citrate, silver-zinc citrate,copper-zinc oxalate, copper-silver oxalate, silver-zinc oxalate,copper-zinc tartarate, copper-silver tartarate, silver-zinc tartarate,copper-zinc malate, copper-silver malate, silver-zinc malate,copper-zinc succinate, copper-silver succinate, silver-zinc succinate,copper-zinc malonate, copper-silver malonate, silver-zinc malonate,copper-zinc maleate, copper-silver maleate, silver-zinc maleate,copper-zinc aspartate, copper-silver aspartate, silver-zinc aspartate,copper-zinc glutamate, copper-silver glutamate, silver-zinc glutamate,copper-zinc glutarate, copper-silver glutarate, silver-zinc glutarate,copper-zinc fumarate, copper-silver fumarate, silver-zinc fumarate,copper-zinc glucarate, copper-silver glucarate, silver-zinc glucarate,copper-zinc polyacrylic acid, copper-silver polyacrylic acid,silver-zinc polyacrylic acid, and combinations thereof. In embodiments,copper, zinc, aluminum and silver salts of organic multi carboxylicacids are suitable for use in accordance with the present disclosure. Inembodiments, suitable compounds can be doped such that the unit cell ofthe coordination compound has zinc or silver constituents dispersedtherein. Such zinc or silver constituents may either substitute anothermetallic constituent or fill a preexisting void in the unit cell.

In embodiments, suitable reaction products can be copper compoundshaving zinc or silver constituents therein. For example, zinc or silvermay either substitute a copper constituent or fill a preexisting void inthe copper compound's unit cell. Suitable non-limiting examples ofcopper compounds which may be used to form multi-metallic complexesinclude copper (II) malonate and any hydrated form thereof such ascopper (II) malonate dihydrate, copper (II) malonate trihydrate, andcopper malonate tetrahydrate. Other suitable non-limiting examples ofsuitable copper active ingredients include copper citrate, copperoxalate, copper tartarate, copper malate, copper succinate, coppermalonate, copper maleate, copper aspartate, copper glutamate, copperglutarate, copper fumarate, copper glucarate, copper polyacrylic acid,and combinations thereof. In embodiments, suitable copper compounds canbe doped such that the unit cell of the compound has zinc or silverconstituents dispersed therein. Such zinc or silver constituents mayeither substitute a copper constituent or fill a preexisting void in theunit cell.

In embodiments, the compositions may contain any active ingredient or beformulated and applied as described in commonly owned U.S. patentapplication entitled Anti-aging Treatment Using Copper-Zinc Compositions(U.S. Ser. No. 11/452,642 filed Jun. 14, 2006) herein incorporated byreference in its entirety. Amino acids may also be used as thepolyfunctional compound. Amino acids are known to those skilled in theart and include those containing at least a dicarboxylic acidfunctionality and an amino functionality. Suitable amino acids includenaturally occurring amino acids and synthetic amino acids. Non-limitingexamples of amino acids include, but are not limited to:aminopolycarboxylic acids (e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid. Aminopolycarboxylic acids, e.g., aspartic acid,β-hydroxyaspartic acid, glutamic acid, β-hydroxyglutamic acid,β-methylaspartic acid, β-methylglutamic acid, β,β-dimethylaspartic acid,γ-hydroxyglutamic acid, β,γ-dihydroxyglutamic acid, β-phenylglutamicacid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid. Polyaminoacids may also beused provided they form complexes with the coordination elementsemployed.

Cu/Zn Malonate Embodiments

In embodiments, malonic acid may be reacted with compounds containingcopper and zinc constituents in an aqueous solution. It has been foundthat where the malonic acid, copper and zinc constituents are present inat least about a 3:1:1 molar ratio, copper-zinc malonates may beproduced in good yield and high crystalline purity.

Malonic acid refers to 1,3-propanedioic acid, a dicarboxylic acid withstructure CH₂(COOH)₂ or:

The ion form of malonic acid, as well as its esters and salts, are knownas malonates. For example, diethyl malonate is ethyl ester of malonicacid. As used herein, the term copper-zinc malonate applies to any saltsubstances formed from malonic acid having copper and zinc constituents.

Suitable ingredients for the formation of copper-zinc malonates includemalonic acid, one or more bases of copper and zinc, and water. In anaqueous reaction solution, suitable salt forms provide copper and zinccations capable of bonding to malonate anions. Other suitableingredients for the formation of copper-zinc malonates will include thereplacement of bases of copper and zinc with the metallic form of copperand zinc. The elemental form of copper and zinc are known as copper andzinc metals and will be dissolved in the acidic water media as theyreact with malonic acid.

One or more compounds containing copper and zinc constituents arepresent in amounts that will contact malonic acid in an aqueoussolution. Suitable compounds for making copper-zinc malonatecompositions in accordance with this disclosure include compoundscontaining complex-forming metal ions of copper and/or zinc. Inembodiments, the aqueous solution may include one or more metalliccompounds, such as cupric carbonate (CuCO₃.Cu(OH)₂), zinc carbonate(3Zn(OH)₂.2ZnCO₃), metallic copper, metallic zinc and combinationsthereof. Basic compounds such as basic zinc compounds, basic coppercompounds, and combinations thereof are also suitable for use inaccordance with the present disclosure. In embodiments, suitable metalbasic compounds are: copper (I) and (II) compounds such as coppercarbonate, copper oxide, and copper hydroxide; and zinc compounds suchas zinc carbonate, zinc oxide, and zinc hydroxide.

It should be understood that the listed compounds are only a smallportion of the compounds suitable for use in accordance with the presentdisclosure. For example, inorganic compounds are suitable provided thatthey provide copper and zinc cations when placed in an aqueous solutionwith the polyfunctional compound. Thus, the foregoing list of compoundsshould be considered a non-limiting, illustrative list.

For carrying out the process, the reaction solution can be prepared bymixing the various ingredients in water where malonic acid and thecoordination element providing compounds may ionize and become morereactive. Water in the mixture is added in amounts sufficient to allowcopper-zinc malonates to form. Where copper and zinc compounds in thereaction mixture are insoluble and form dispersions (such as at coolertemperatures), mixing and heating steps can be applied to bring thereactants to 40-100° C. in order to solubilize the reactants and startreactions. As a result, reaction rates may be enhanced through energyinput such as microwave heating or addition of boiling water dissolver.The input of the energy may take place through any instrument capable ofheating the aqueous reaction mixture. The copper-zinc malonate complexesformed in solution may be immediately separated so that their productioncan take place in a continuous process. Due to the short reaction timeand the rapid crystallization of the copper-zinc malonate product, theconversion may be carried out continuously, and the recovery of theresultant solid product may take place by any conventional manner suchas filtering, centrifugation, or sedimentation.

In the production of the reaction mixture, the concentration of thepolyfunctional compound and that of the copper and zinc constituents maybe pre-selected so that the total concentration of product formedexceeds the solubility equilibrium. This will result in productprecipitating from solution in solid form for easy collection.

In embodiments, the final composition may be a deep blue crystal havinggood yield and substantial crystalline purity. Suitable copper-zincmalonate forms in accordance with the present disclosure include anysalt formed from the neutralization of malonic acid by one or morecopper containing molecules and one or more zinc containing molecules.Illustrative examples include salt formed by the neutralization ofmalonic acid by cupric carbonate (CuCO₃·Cu(OH)₂), and zinc carbonate(3Zn(OH)₂.2ZnCO₃) in an aqueous solution. Here zinc may be added first,followed by copper in order to obtain the salts of the presentdisclosure.

In embodiments, the copper-zinc malonates may be one or more ioniccompounds formed by joining one or more independent copper molecules orions and one or more independent zinc molecules or ions to a centralunit by ionic bonds. For example, the copper-zinc malonate may be in theform of a trinuclear cation, where structurally independent copper andzinc hydrates are bridged by a central unit such as an octahedraldiaquadimalonatocopper (II) unit. However, various coordination modesare possible depending on the source of the copper and zinc andsynthesis conditions. In embodiments, the central unit malonate ion maybe a multi-membered ring such as eight-membered ring, six-membered ring,and four-membered metalocycle for bridging or chelating functionsbetween the copper and zinc constituents. Accordingly, the crystalstructures of copper-zinc malonates can be very diverse, from ionic tothree-dimensional polymers. In embodiments, the copper-zinc malonatescan be found in several hydrate, and polymorphic forms.

In embodiments, the process parameters are especially advantageous ifthe polyfunctional compound is added to excess in comparison to themetal counter cation constituents. Depending on the desired complex, thelatter are added so that the molar ratio of polyfunctional compound tometal ions is approximately 3:2.

Formulations Containing the Multi-Metallic Complex

The resulting compounds having at least two metal cations in the samemolecule serve as active ingredients in the multi-metalcomplex-containing composition used in the presently described regimensfor treatment of skin. Such active ingredients may be combined withnumerous ingredients to form products of numerous chemical applications,such as catalytical agents, crosslinking of polymers, superconductingelectrical materials, pharmaceutical drugs, food supplements, etc. Theactive ingredients in suitable compositions can be topically applied tothe skin, or into other tissues of humans or other mammals. Suchproducts may include a dermatologically or pharmaceutically acceptablecarrier, vehicle or medium, for example, a carrier, vehicle or mediumthat is compatible with the tissues to which they will be applied. Theterm “dermatologically or pharmaceutically acceptable,” as used herein,means that the compositions or components thereof so described aresuitable for use in contact with these tissues or for use in patients ingeneral without undue toxicity, incompatibility, instability, allergicresponse, and the like. In embodiments, compositions in accordance withthe present disclosure can contain any ingredient conventionally used incosmetics and/or dermatology. In embodiments, active ingredients may beformulated to provide crystals in solution, as well as solid forms.

In embodiments, products containing a reaction product in accordancewith the present disclosure as an active ingredient can be in the formof solutions, emulsions (including microemulsions), suspensions, creams,lotions, gels, powders, or other typical solid or liquid compositionsused for treatment of damaged skin. Such compositions may contain, inaddition to the reaction product in accordance with this disclosure,other ingredients typically used in such products, such asantimicrobials, moisturizers and hydration agents, penetration agents,preservatives, emulsifiers, natural or synthetic oils, solvents,surfactants, detergents, gelling agents, emollients, antioxidants,fragrances, fillers, thickeners, waxes, odor absorbers, dyestuffs,coloring agents, powders, viscosity-controlling agents and water, andoptionally including anesthetics, anti-itch actives, botanical extracts,conditioning agents, darkening or lightening agents, glitter,humectants, mica, minerals, polyphenols, silicones or derivativesthereof, sunblocks, vitamins, and phytomedicinals.

As an illustrative example, products can be formulated to containmulti-metal complexes in amounts from about 0.001 to about 5% by weightof the total composition. In embodiments, products can be formulated tocontain multi-metal complexes in an amount from about 0.05 to about 1.0%by weight of the total composition. In other embodiments, the amount ofmulti-metal complexes is from about 0.1 to about 0.5% by weight of thetotal composition. Here, the multi-metal complexes present may be in apharmaceutically acceptable salt form. Other active ingredients may beprovided in the formulations at the same concentrations.

Table 2 below provides illustrative emulsion formulations suitable forthe composition containing one or more multi-metal complexes.

TABLE 2 Illustrative Phase Ingredient compound(s) Suitable range WaterSolvent Water from about 50% to Phase Polyalkylene about 80% by weightglycol of the emulsion composition Water Humectant Glycerine from about0.05% to Phase Polyalkylene about 10% by weight glycol of the emulsioncomposition Water Preservative Phenoxyethanol from about 0.01% to PhaseMethylparaben about 5.0% by weight Ethylparaben of the emulsioncomposition Water Emollient Dipropylene from about 0.01% to Phase glycolabout 10% by weight of the emulsion composition Water Buffer NaOHsolution from about 0.01% to Phase about 10% by weight of the emulsioncomposition Oil Phase Solvent isohexadecane from about 5% to about 20%by weight of the emulsion composition Oil Phase Emollient Isohexadecanefrom about 2% to Coco-caprylate/ about 20% by weight caprate C₁₃-C₁₅ ofthe emulsion alkane Ethylhexyl composition palmitate Oil PhaseEmulsifier Glyceryl Stearate from about 0.1% to Polyalkelene about 5% byweight glycol stearate of the emulsion composition Oil Phase ThickenerCetyl alcohol from about 1% to Stearyl alcohol about 10% by weightSimulgel NS* of the emulsion composition Oil Phase PreservativePropylparaben from about 0.01% to Butylparaben about 5% by weight of theemulsion composition Oil Phase Miscellaneous** Blueberry extract fromabout 0.0001% Mica to about 5% by Titanium dioxide weight of the Ironoxide emulsion composition Talc Alumina Silica *Commercially availablefrom Seppic Corporation, Fairfield, N.J.. **May be present as FlamencoSatin Green P860, commercially available from Engelhard Corporation,Iselin, NJ; Kobo BPD 500 commercially available from Kobo Products,South Plainfield, NJ and/or Cloverleaf AR-80 commercially available fromPresperse Inc. Somerset, NJ.Retinoid Compositions

Prior to application of the composition containing a multi-metalcomplex, the skin is treated in accordance with the present regimens byapplication of both a retinoid and hydroquinone. The retinoid may beapplied as a composition containing a retinoid and a dermatologically orpharmaceutically acceptable carrier.

Non-limiting examples of suitable retinoids include isotretinoin,retinal, retinol, retinoic acid, retinyl acetate, retinyl palmitate,retinyl propionate, synthetic retinoid mimics, and tretinoin. Inembodiments, the retinoid is tretinoin. The retinoid may be present inthe composition in an amount ranging from about 0.005% to about 1.0% byweight of the composition. In one embodiment, for example, the retinoidis present in an amount ranging from about 0.025% to about 0.75% byweight. In another embodiment, the retinoid is present in an amount ofabout 0.50% by weight. The retinoid may be formulated into a compositionsuitable for topical application using conventional ingredientsformulated using techniques within the purview of those skilled in theart.

Suitable retinoid compositions for use as the second composition arecommercially available and include, but are not limited to RETIN-AMICRO® (Commercially available from Orthoneutrogena, Skillman, N.J.),RENOVA® (Commercially available from Orthoneutrogena, Skillman, N.J.),AVAGE® (Commercially available from Allergan, Inc., Irvine, Calif.),TAZARAC® (Commercially available from Allergan, Inc., Irvine, Calif.),TAZAROTENE® (Commercially available from Allergan, Inc., Irvine,Calif.), ADAPALENE® (Commercially available from Galderma Laboratories,LP, Fort Worth, Tex.), DIFFERIN® (Commercially available from GaldermaLaboratories, LP, Fort Worth, Tex.), AVITA® (Commercially available fromRenederm Inc., Foster City Calif.), AFFIRM® (Commercially available fromCosMedix, LLC, Atlanta, Ga.).

In accordance with the present regimens, hydroquinone is also applied tothe skin prior to application of the composition containing themulti-metal complex. Hydroquinone can be applied before, after orsimultaneously with the retinoid.

The hydroquinone compositions of the present disclosure containhydroquinone or a hydroquinone derivative and a dermatologically orpharmaceutically acceptable carrier. Hydroquinone is a well-knowncompound having the general formula:

The hydroquinone is present in amounts that provide a benefit to theskin of a user. In embodiments, hydroquinone is present in an amountsufficient to effect depigmentation. Generally, hydroquinone in amountsfrom about 0.1 to about 10% by weight of the total composition issuitable. In embodiments, hydroquinone is present in an amount fromabout 1 to about 5% by weight of the total composition. In yet otherembodiments, hydroquinone is present in an amount from about 2.5 toabout 4.5% by weight of the total composition.

Suitable hydroquinone compositions for use as in the present treatmentregimens include, but are not limited to commercially available productssuch as, for example GLYTONE® Fading Lotion (2% HQ), MELA-D® by LaRoche-Posay, ESSENTIAL SKIN LIGHTENER® by Exuviance, PIGMENT GEL—Phaze13 by PCA Skin®, 6% SKIN BLEACHING CREAM by Physician's Complex,CONDITIONING GEL PLUS by Biomedic, PIGMENTAION FADER by pH Advantage,LUMEDIA by Lumedia, POTENT SKIN LIGHTENING GEL COMPLEX by Peter ThomasRoth, HQ SKIN LIGHTENING GEL PHA by NeoStrata, SKIN LIGHTENING TREATMENTby B. Kamins,

In the context of the present disclosure, the term “hydroquinonederivative” is understood to mean compounds that are substitutedhydroquinones wherein the substitution does not significantly affect oneor more of the enzyme inhibition function of hydroquinone, themelanocidal activity of hydroquinone or the reducing capacity of thehydroquinone. The hydroquinone derivatives have the formula:

wherein R is a group that maintains the skin lightening functionality ofhydroquinone and results in a non-toxic compound suitable for topicalapplication to the skin of a user.

In embodiments, the R group results in the production of a glycoside ofhydroquinone. In such embodiments R represents a pentose residue, ahexose residue, an amino sugar residue, or a uronic acid residue, or themethylated product thereof in a skin treatment base. Techniques for thepreparation of such compounds are disclosed in U.S. Pat. No. 5,310,730,the entire contents of which are incorporated herein by this reference.Arbutin is an example of one suitable glycoside of hydroquinone.

Other examples of suitable substituted hydroquinones include monoalkylethers and hydroquinone monoaryl ethers. Such hydroquinone ethers aredescribed in Japanese Patent Applications Nos. JP-06 192 062 and JP-61159 943; ethers of hydroquinone and of a heterocyclic alcohol, asdescribed in U.S. Pat. No. 6,139,854, which is also incorporated in itsentirety herein by reference; (2,5-dihydroxyphenyl) carboxylic acidderivatives described, for example, in application U.S. Pat. No.5,449,518, which is also incorporated in its entirety herein byreference; hydroquinone which is substituted, in particular, withalkylthio or alkoxy groups.

Non-limiting examples of hydroquinone derivatives include:2,5-dihydroxyphenyl propionic acid, the ethyl ester of2,5-dihydroxyphenyl propionic acid; the lauryl ester of2,5-dihydroxyphenylpropionic acid; methyl2,5-dihydroxy-3,4-dimethylphenyl acetate; 2,5-dihydroxy-4-methylphenylacetic acid; alkyl esters of 2,5-dihydroxy-4-methylphenyl acetic acid;2,5-dihydroxy-4-methylphenyl propionic acid; ethyl ester of2,5-dihydroxy-4-phenylpropionic acid; 2,5-dihydroxy-4-methylbenzoicacid; methyl ester of 2,5-dihydroxy-4-methylbenzoic acid; ethyl ester of2,5-dihydroxy-4-methylbenzoic acid; 2,5-dihydroxy-4-ethylbenzoic acid;2,5-dihydroxy-4-methoxybenzoic acid; methyl ester of2,5-dihydroxy-4-methoxybenzoic acid; 2,5-dihydroxy-4-ethoxybenzoic acid;3-(2,5-dihydroxy-4′-methylphenyl)-1-N-(.omega.-carboxydecyl)propylamide;2,5-dihydroxy-4-methylphenylbutanoic acid;2,5-dihydroxy-4-methylpenylhexanoic acid;2,5-dihydroxy-4-methoxyphenylacetic acid; methyl ester of2,5-dihydroxy-4-methoxyphenylacetic acid;2,5-dihydroxy-4-methoxybenzylamide; methyl2,5-dihydroxy-3-methoxyphenylacetate2,5-dihydroxy-3-methoxyphenylpentadecylic acid; methyl ester of2,5-dihydroxy-3-methoxyphenylpentadecylic acid;2,5-dihydroxyphenylbutanoic acid; methyl ester of2,5-dihydroxyphenylbutanoic acid; 2,5-dihydroxyphenylbutylamide2,5-dihydroxyphenylpentanoic acid; 2,5-di hydroxyphenylhexanoic acid;2,5-dihydroxyphenyloctanoic acid; 2,5-dihydroxyphenyldecylic acid;methyl ester of 2,5-dihydroxyphenyldecylic acid;2,5-dihydroxyphenylundecylic acid; methyl ester of2,5-dihydroxyphenylundecylic acid;2,5-dihydroxy-3,4-dimethylphenylacetic acid;ethyl-2,5-dihydroxy-4,6-dimethylphenylacetate;2-(2,5-dihydroxy-4-methoxyphenyl)-N-octylacetamide;6-(2,5-dihydroxy-4-methoxyphenyl)hexanoic acid;4-[(6-methoxyetrahydro-2H-pyran-2-yl)oxyphenol;4-Rtetrahydro-2H-pyran-2-ypoxy]phenol; and4-[(tetrahydro-2H-thiopyran-2-yl)oxy]phenol.

In embodiments, the hydroquinone derivative is selected from:2,5-dihydroxyphenylpropionic acid;2,5-dihydroxy-3,4-dimethylphenylacetic acid; methyl2,5-dihydroxy-3,4-dimethylphenylacetic acid;2,5-dihydroxy-4-methylphenylacetic acid;2,5-dihydroxy-3,4-dimethylphenylpropionic acid; methyl2,5-dihydroxy-4-methylphenylacetate; ethyl2,5-dihydroxy-4-methylphenylacetate; propyl2,5-dihydroxy-4-methylphenylacetate; isopropyl2,5-dihydroxy-4-methylphenylacetate; butyl2,5-dihydroxy-4-methylphenylacetate; pentyl2,5-dihydroxy-4-methylphenylacetate; isoamyl2,5-dihydroxy-4-methylphenylacetate; and2-(2,5-dihydroxy-4-methylphenyl)-N-octylacetamide.

In embodiments, retinoid and hydroquinone are sequentially applied. Inother embodiments, the retinoid is provided separately from and premixedwith a hydroquinone-containing blending composition prior to applicationto the décolletage. When provided separately, the retinoid need not beformulated for topical application, but rather the blending compositionmay provide the necessary pharmaceutically or dermatologicallyacceptable carrier.

The hydroquinone-containing blending composition is designed to beblended with treinoin to be applied to the skin. A particularly usefulblending composition contains an active ingredient in a base compositionof water, glycerin, cetyl alcohol, PPG-2 myristyl ether propionate,sodium lauryl sulfate, TEA-salicylate, lactic acid, phenyl trimethicone,tocopheryl acetate, sodium metabisulfite, ascorbic acid, methylparaben,saponins, disodium EDTA, BHT and propylparaben. One suitablehydroquinone-containing blending composition is OBAGI NU-DERM® BLENDER®commercially available from OMP, Inc. of Long Beach, Calif.

Suitable blending compositions may also be made in accordance with theingredients identified in Table 1.

TABLE 1 % of total Compound composition Purified water 70-85Preservatives .01-1.5 Chelating Agent .01-0.5 Humectants  1-10 Anionic.01-5   Surfactants Nonionic .01-5   Surfactants Organic Acid .01-5  C12-C18 Alkyl  2-50 Alcohols Antioxidants .01-10  Reducing Agents.01-5   Emollient  1-10 Hydroquinone  0.0-10%

Suitable preservatives for use in the blending composition furtherinclude: benzoic acid, benzyl alcohol, butylparaben, diazolidinyl urea,2,3-Imidazolidinedione, isopropylparaben, isobutylparaben,methylparaben, propylparaben, sodium butylparaben, sorbic acid, orcombinations of these preservatives.

Suitable chelating agents for use in the blending composition furtherinclude: citric acid, edetate disodium, ethylenediaminetetraacetic acid,etidronic acid sodium dihydroxyethylglycinate, nitrilotriacetic acid,and combinations of these agents.

Suitable emulsifiers for use in the blending composition furtherinclude: cetearyl alcohol, ethoxylated fatty alcohols, PEG-1000monocetyl ether, alkyl trimethyl ammonium bromide, polyol ester glycerolmonostearate, potassium stearate, sodium lauryl sulfate, sodium cetearylsulfate, saponins, and combinations of these agents.

Suitable humectants for use in the blending composition further include:glycerin, diglycerin, triglycerin, polyglycerin, polypropylene glycol,polyethylene glycol, ethylene glycol, diethylene glycol, triethyleneglycol, propylene glycol, dipropylene glycol, hexylene glycol,1,3-butylene glycol, 1,4-butylene glycol, ethylene glycol monoalkylether, diethylene glycol monoalkyl ether, glucose, maltose, sucrose,lactose, xylitose, xylitol, sorbitol, mannitol, maltitol, panthenol,pentaerythritol, hyaluronic acid, and combinations of these humectants.

Suitable pH adjusters for use in the blending composition furtherinclude: citric acid, phosphoric acid, lactic acid, glycolic acid, andcombinations of these pH adjusters.

Suitable antioxidants for use in the blending composition furtherinclude: ascorbyl palmitate, 2,6 ditertiarybutyl-4-methyl phenol,butylated hydroxyanisole, tocopherol, tocopheryl acetate, propylgallate, and combinations of these antioxidants.

Suitable emollients for use in the blending composition further include:cetyl alcohol, stearyl alcohol, liquid hydrocarbon oil, liquid naturaloil, liquid fatty alcohol, liquid fatty acid, liquid fatty acid ester,liquid silicone oil, paste wax, and combinations of these emollients.

Suitable reducing agents for use in the blending composition furtherinclude: ascorbic acid, propyl gallate, sodium metabisulfite, andcombinations of these reducing agents.

Treatment Regimens

Regimens for treatment of the décolletage in accordance with the presentdisclosure include sequential application to the décolletage of aretinoid and hydroquinone followed by the application of the compositioncontaining a multi-metal complex. It should, of course, be understoodthat the multi-metal complex may be applied before application of theretinoid and/or hydroquinone.

In embodiments the treatment regimen involves a morning application andan evening application. The morning application includes the sequentialapplication of a retinoid and hydroquinone followed by the applicationof the composition containing a multi-metal complex. The eveningapplication involves application of hydroquinone followed by theapplication of the composition containing a multi-metal complex.Alternatively, the morning and evening treatments can be switched, withthe morning application involving application of hydroquinone followedby the application of the composition containing a multi-metal complexand the evening application including application of a retinoid andhydroquinone followed by the application of a composition containing amulti-metal complex. It should, of course, be understood that themorning and evening treatment regimens may be reversed.

In embodiments, the retinoid and hydroquinone are applied sequentially.In other embodiments, the retinoid and hydroquinone are applied as apre-mix prepared immediately before application to the décolletage. Insuch embodiments, a retinoid is provided and a hydroquinone-containingblending composition is provided. The retinoid is mixed with thehydroquinone-containing blending composition immediately prior toapplication to the décolletage. Thus, in embodiments, the presenttreatment regimens include, pre-mixing a retinoid with ahydroquinone-containing blending composition, applying the pre-mixedformulation to the skin of the décolletage, and applying a compositioncontaining a multi-metal complex to the skin of the décolletagepreviously treated with the pre-mixed composition.

In embodiments the treatment regimen involves a morning application andan evening application. The morning application includes, pre-mixing aretinoid with a hydroquinone-containing blending composition, applyingthe pre-mixed formulation to the skin of the décolletage, andapplication of the composition containing a multi-metal complex to theskin of the décolletage previously treated with the pre-mixedcomposition. The evening application involves application of thehydroquinone-containing blending composition (without retinoid) to theskin of the décolletage followed by application of the compositioncontaining a multi-metal complex to the skin of the décolletagepreviously treated with the blending composition. Alternatively, themorning and evening treatments can be switched, with the morningapplication involving application of the hydroquinone-containingblending composition (without retinoid) to the skin of the décolletagefollowed by application of the composition containing a multi-metalcomplex to the skin of the décolletage previously treated with theblending composition and the evening application including pre-mixing aretinoid with a hydroquinone-containing blending composition, applyingthe pre-mixed formulation to the skin of the décolletage and theapplication of the composition containing a multi-metal complex to theskin of the décolletage previously treated with the pre-mixedcomposition. It should, of course be understood that separate retinoidand hydroquinone compositions can be applied sequentially in each of theforegoing regimens rather than forming a pre-mix composition.

Pre-packaged kits may be provided containing the products of thetreatment regimen. In embodiments, the kit includes a plurality ofseparate containers, each containing at least one active agent useful ina combination therapy for the treatment of skin, especially décolletage.The kit contains a first container containing a retinoid, a secondcontainer containing a hydroquinone, and a third container containing acomposition that includes a multi-metal complex. The containers of thekit may be enclosed within a common outer packaging, such as, forexample a cardboard or plastic box or a shrink wrap outer skin enclosingthe various containers. In embodiments, the retinoid, hydroquinone, andcomposition containing a multi-metal complex are each individuallyformulated in a dermatologically acceptable carrier for topicalapplication. In other embodiments, the composition containing amulti-metal complex and the hydroquinone are formulated for topicalapplication, and the retinoid is provided for mixing with thehydroquinone before application. In embodiments, kits contain a firstset of products to be used with a first treatment regimen and a secondset of products to be used with a second treatment regimen as describedabove.

The kits may be in the form of a consumer package or prescriptionpackage which provides the products described above. In embodiments, acombination of a consumer package with prescription product(s) may beobtained. The package may provide instructions or directions on how touse and/or combine the products for one or more treatment regimens asdescribed above.

The regimens in accordance with this disclosure can be used to treat thedécolletage or any other area of the skin. As used herein the word“treat,” “treating” or “treatment” refers to using regimens of thepresent disclosure prophylactically to prevent outbreaks of undesirabledermatological conditions, or therapeutically to ameliorate an existingdermatological condition, and/or extend the duration of the aestheticbenefit of a skin procedure. As used herein “undesirable skin condition”refers to any skin condition that may require treatment of any sort,including skin having one or more undesirable appearances and/ordisagreeable tactile sensations. The term further refers to anycosmetically undesirable skin condition, as well as any undesirablediseased or damaged skin condition.

Non-limiting examples of undesirable skin conditions which can betreated with the topical application of compositions in accordance withthe present disclosure include: acne vulgaris (pimples); atopicdermatitis; birthmarks; cafe-au-laits spots; common benign skin tumorsor growths; common skin conditions around the eyes such as eyelidcontact dermatitis, atopic dermatitis, bacterial skin infection(impetigo or conjunctivitis), xanthelasma, syringoma, skin tags, milia,Naevus, and/or portwine stains; common skin condition associated withhousework such as irritant contact dermatitis, allergic contactdermatitis, contact urticaria, fungal infections, paronychia, and/orviral warts; common diseases of the scalp such as seborrhoeicdermatitis, psoriasis of the scalp, lichen planus, discoid lupuserythematosus (DLE), alopecia areata, seborrhoeic keratoses (seborrhoeicwarts, age spots), solar keratoses, angiosarcoma, fungal infection(ringworm, tinea Capitis), bacteria infections of the hair follicles(folliculitis, boils), and/or shingles (Herpes Zoster); common diseasesin children such as atopic dermatitis, atopic eczema, discoid eczema,pityriasis alba, vitiligo, and/or alopecia areata; common diseases ofthe mouth and lips such as oral candidiasis, oral leukoplakia, apthousulcers, and/or oral lichen planus; common skin problems in elderly suchas appearance and texture changes, senile purpura, xerosis/asteatoticeczema, skin Infections/infestations, pigmentary changes, blisteringdisorders, non-cancerous skin growths, cancerous skin growths, adversedrug reaction, and/or stasis dermatitis; common viral warts; contactallergy; diaper candidiasis, drug allergy, folliculitis; freckles;fungal infections of the skin such as white spot, athlete's foot, jockitch, and/or moniliasis/candidiasis; guttate hypomelanosis; hair loss;hand eczema; impetigo; lines, crow's feet, wrinkles, etc.; melasma;molluscum contagiosum; occupational skin disease such as irritationand/or allergy; post-Inflammatory pigmentation; psoriasis; rosacea;shingles; skin cancers; skin diseases in diabetes mellitus; skindiseases in pregnancy; skin disorders caused by cosmetics such asirritant contact dermatitis and/or allergic contact dermatitis, cosmeticinduced pimples (acne), sunscreens allergy, and/or special cosmeticallergies, solar lentigenes; tinea capitis; viral warts; vitiligo; andcombinations of these undesirable skin conditions.

In embodiments, compositions in accordance with the present disclosureare suitable for treating diseased skin, or any condition which canresult from the excessive amount of pathogens such as fungi, viruses,and or bacterium affecting the skin in any way.

In embodiments, an undesirable skin condition is skin that has a roughtexture or uneven appearance such as psoriasis, bumps, razor burns,and/or patches.

The particular concentration in the compositions, generally depends onthe purpose for which the composition is to be applied. For example, thedosage and frequency of application can vary depending upon the type andseverity of the skin condition. In general, patients are treated bytopically applying the hydroquinone, retinoid and multi-metalcomplex-containing compositions described herein to skin of thedécolletage suffering from a condition until the treatment goals areobtained. However, the duration of the treatment can very depending onthe severity of the condition. For example, treatments can last severalweeks to months depending on whether the goal of treatment is to reduceor eliminate the skin condition.

In treatment embodiments, the compositions and methods in accordancewith the present disclosure can be combined with other skin treatmentsystems. For example, the multi-metallic salt complexes and be appliedto skin in combination with skin treatment systems such as the OBAGINU-DERM® skin treatment system and related Obagi skin care products fromO.M.P. Inc. of Long Beach Calif. More specifically copper-zinc malonatecompositions can be combined with the OBAGI NU-DERM® skin treatmentsystem in order to promote the beneficial affects of that system. Asthose skilled in the art will appreciate, the OBAGI NU-DERM® skintreatment system includes the use of a series of products referred to byO.M.P. Inc. as Foaming Gel (Cleanser) or a Gentle Cleanser, a Toner,Clear, EXFODERM® or EXFODERM® Forte, BLENDER®, and Healthy SkinProtection SPF 35 or SUNFADER®. Details regarding these products and themethod of using them can be found at the official website of ObagiMedical Products, Inc. The active ingredients and formulations inaccordance with the present disclosure may either be incorporated intoother product formulations, or applied to the skin before, after, and/orduring other skin treatments.

The following non-limiting examples further illustrate compositions andmethods in accordance with this disclosure.

Example 1

Example 1 below shows suitable ingredients of a reaction mixture forforming copper-zinc malonates for use in the multi-metalcomplex-containing composition in accordance with the presentdisclosure.

Ingredient Amount Malonic acid 1.8 g cupric carbonate 0.632 g zinccarbonate 0.676 g Water 100 ml

Example 2

1.8 g of malonic acid (CH₂(COOH)₂) was combined with 0.632 grams ofcupric carbonate (CuCO₃.Cu(OH)₂), 0.676 g of zinc carbonate(3Zn(OH)₂.2ZnCO₃), and 100 ml of water to form a dispersion. Thesolution was heated until the reactants went into solution. Well-defineddeep-blue crystals precipitated and were separated from the aqueoussolution of malonic acid, cupric carbonate, and zinc carbonate (3:1:1molar ratio) that had been kept at room temperature. Duel salt wasformed by replacing acid groups with copper and zinc cations in the samemolecule. The deep blue crystals were found to have a melting point ofabout 210° C.

Sample prepared as per ASTM-D-1971-95 (herein incorporated by referencein its entirety) and analyzed by method 6010 (I.C.P.) (hereinincorporated by reference in its entirety) showed 16.5% copper and 12.4%zinc.

Example 3

1.8 g of malonic acid (CH₂(COOH)₂) was combined with 0.632 grams ofcupric carbonate (CuCO₃.Cu(OH)₂), 0.676 g of zinc carbonate(3Zn(OH)₂.2ZnCO₃), and 100 ml of boiling water. Well-defined deep-bluecrystals were separated from the aqueous solution of malonic acid,cupric carbonate, and zinc carbonate (3:1:1 molar ratio) that had beenkept at room temperature for 1 week.

Example 4

3 moles of malonic acid is thoroughly mixed with 1 mole of copper ascupric carbonate and 1 mole of zinc as zinc carbonate in a stirred tankreactor containing 100 ml of heated water (approximately 95-100° C.).After a short reaction time with cooling, copper-zinc malonateprecipitates out of solution with a high yield. A filtration step isused to isolate the complex as a powder. Deep blue crystals are obtainedhaving a melting point of about 210° C.

Example 5

In embodiments, copper-zinc malonate formulations suitable for use asthe multi-metal complex-containing composition in the present regimenshave the following make-up:

COMPONENT % BY WEIGHT Copper-zinc malonate* 0.1% (Active ingredient)Glycerine 3.0% Propylene Glycol 25.0% Distilled Water 71.9%

Example 7

Compositions containing multi-metal complex are prepared having theingredients listed in Table 4 below in the amounts indicated.

TABLE 2 Amount as percentage Phase Ingredient Of entire emulsionformulation Water Phase Water 70.656%   Water Phase PEG-6¹   3% WaterPhase Glycerine 0.5% Water Phase Methylparaben 0.2% Water PhasePhenoxyethanol .05 Water Phase Dipropylene glycol 1.5% Water PhaseEthylparaben 0.1% Oil Phase Isohexadecane² 6.5% Oil PhaseCoco-caprylate/caprate³   3% Oil Phase C₁₃-C₁₅ alkane⁴   3% Oil PhaseEthylhexyl palmitate   3% Oil Phase Lipomulse 165⁵ 2.5% Oil Phase Cetylalcohol 0.5% Oil Phase Stearyl alcohol 1.5% Oil Phase Propylparaben 0.2%Oil Phase Butylparaben 0.05%  Oil Phase Flamenco Satin Green 0.01% P860⁶ Oil Phase Kobo BPD 500⁷ 0.01%  Oil Phase Coverleaf AR-80⁸ 0.001% ¹Carbowax 300, commercially available from Dow Chemical Company,Midland, MI. ²Permethyl 101A, commercially available from Presperse Inc.Somerset, NJ. ³Cetiol LC, commercially available from Cognis Chemical,Ambler, PA. ⁴Gemseal 25, commercially available from Presperse Inc.Somerset, NJ. ⁵Commercially available from Lipo Chemicals, Inc.,Paterson, NJ. ⁶Commercially available from Engelhard Corporation,Iselin, NJ. ⁷Commercially available from Kobo Products, SouthPlainfield, NJ. ⁸Commercially available from Presperse Inc. Somerset,NJ.

To prepare the composition, the water phase ingredients are mixed atroom temperature (25-35° C.) in a first container. The oil phaseingredients are then combined in a second container with heating to70-75° C. in a second container. The water phase is then heated to70-75° C. and added to the oil phase with stirring. The multi-metalliccomplex prepared in accordance with Example 2 at an amount equivalent to1.1528% of the entire emulsion is added with stirring at 80° C. SimugelNS at an amount equivalent to 2% of the entire emulsion is added withstirring at 55-60° C. Blueberry extract at an amount equivalent to 0.02%of the entire emulsion is added with stirring at 40-45° C. and the pH isadjusted with a 5% NaOH solution to a pH of 4.2-4.4.

Example 8

A randomized controlled study was conducted to evaluate the tolerabilityof a treatment regimen in accordance with the present disclosure. Thetreatment regimen included the application of the composition of Example7, the commercially available OBAGI NU-DERM® BLENDER® containing 2%hydroquinone and tretinoin, either at 0.025% or 0.05%. Forty women inthe range of 40 to 60 years old participated in the study, with half ofthe subjects using 0.025% tretinoin and half of the subjects using 0.05%tretinoin. The tolerability was assessed by the subjects themselves(self-assessment) and by trained clinicians who applied the treatment asdiscussed below.

Each subject was seen at a clinic everyday (except weekend and holidayswhen the clinic is closed) from the initial, baseline visit through day21 to have the morning application treatment system products appliedunder the supervision and direction of a clinic staff member. Eachsubject applied the evening application of the treatment system productsat home. On weekends and holidays when the clinic was closed eachsubject applied both the morning and evening application at home.

The order of the morning application of the treatment system products atthe clinic was:

-   -   1) A “Dime” size amount of the hydroquinone-containing blender        was squeezed and a “dime” size amount of the tretinoin onto the        palm of the hand and mix together with the fingertip. Then using        the fingertips from the opposite hand, the pre-mixed product was        applied evenly to the décolletage, and finished by feathering        the product up the neck.    -   2) Two pumps of the multi-metallic complex-containing        composition were pumped into the palm of the hand. Using the        fingertips from the opposite hand, the entire amount of product        was applied to the décolletage, and finished by feathering the        product liberally up the neck.    -   3) Hands were washed after applying the treatment system        products and care taken not to touch the eyes or mouth.

The order of the evening application of the treatment system products athome was:

-   -   1) A “Dime” size amount of the hydroquinone-containing blender        was squeezed out onto the fingertip and applied evenly to the        décolletage, and finished by feathering the product up the neck.    -   2) Two pumps of the multi-metallic complex-containing        composition were pumped into the palm of the hand. Using the        fingertips from the opposite hand, the entire amount of product        was applied to décolletage, and finished by feathering the        product liberally up the neck.    -   3) Hands were washed after applying the treatment system        products with care to avoid touching the eyes or mouth area.

At least 8 hours were allowed between the morning and eveningapplications.

Both treatment regimens were well tolerated by the subjects, with the0.025% tretinoin regimen being better tolerated than the 0.05% tretinoinregimen.

While several embodiments of the disclosure have been described, it isnot intended that the disclosure be limited thereto, as it is intendedthat the disclosure be as broad in scope as the art will allow and thatthe specification be read likewise. Therefore, the above descriptionshould not be construed as limiting, but merely as exemplifications ofembodiments. Those skilled in the art will envision other modificationswithin the scope and spirit of the claims appended hereto.

What is claimed is:
 1. A kit comprising: a first container containing afirst composition comprising a retinoid and a dermatologically orpharmaceutically acceptable carrier, a second container containing asecond composition comprising a hydroquinone and a dermatologically orpharmaceutically acceptable carrier, a third container containing athird composition comprising a multi-metal complex and adermatologically or pharmaceutically acceptable carrier wherein themulti-metal complex comprises a central unit, wherein the central unitis derived from at least one compound selected from polycarboxylic acidsand amino acids having at least two carboxylic acid groups and thecenter unit bridges one or more copper molecules and one or more zincmolecules by coordinate bonding, the first, second and third containersbeing enclosed within a common outer packaging, and instructionsdirecting a user to apply each of the first, second and thirdcompositions to a non-facial area of the skin of a user.
 2. The kitaccording to claim 1, wherein the area of non-facial skin is thedécolletage.
 3. The kit according to claim 1, wherein the instructionsdirect the user to sequentially apply the first and the secondcompositions to the area of non-facial skin.
 4. The kit according toclaim 1, wherein the instructions direct the user to simultaneouslyapply the first and the second compositions to the area of non-facialskin.
 5. The kit according to claim 1, wherein the retinoid is retinolor tretinoin.
 6. The kit according to claim 1, wherein the hydroquinoneis arbutin.
 7. The kit according to claim 1 wherein the instructionsdirect the user to: a) apply the first, second and third compositions asa first treatment; b) wait a pre-determined period of time; and c) applythe second and third compositions as a second treatment.
 8. The kitaccording to claim 7, wherein the instructions direct the user to waitat least four hours between the first treatment and the secondtreatment.
 9. The kit according to claim 7, wherein the instructionsdirect the user to perform the first treatment in the morning and thesecond treatment in the evening.
 10. The kit according to claim 7,wherein the instructions direct the user to pre-mix the first and thesecond compositions immediately prior to administering the firsttreatment to the area of skin.